Tyrer-Cuzick Lifetime Risk Is Not Associated With Non-BRCA1/2 Pathogenic Variants for Breast Carcinoma.

Background: The Tyrer-Cuzick (TC) or IBIS risk calculator is a widely used tool to estimate the probability of developing breast cancer. The latest version incorporates various factors to assess the risk of breast cancer, including family history, personal history, breast density, and past medical history. The TC is commonly used to guide patients toward further diagnostic imaging, genetic testing, chemoprevention, or risk-reducing surgery. However, it is unclear whether the TC is associated with non-BRCA1/2 pathogenic variants (PVs) in breast cancer susceptibility genes. Methods: A population of 964 patients with TC was evaluated for 12 PVs and variants of unknown significance (VUS) using lab-agnostic genetic testing. Patients were enrolled from 2019 to 2022. Historical TC were used for the subgroup of patients who developed breast cancer after enrollment. TC scores were compared between the three patient cohorts that had BRCA gene mutations, non-BRCA PVs, and negative for PVs, using the Kruskal-Wallis test followed by pairwise comparison using DSCF adjustment for multiple comparisons. Data collection for patient cohorts occurred simultaneously and was only separated in analysis. Logistic regression was carried out to predict BRCA versus negative in a model with TC scores, as well as non-BRCA versus negative. Area under the receiver operating characteristic (ROC) curve (AUC) was calculated to assess model fit. Results: This study found an average TC of 7.71%. A family history of cancer was noted in 78.30% of patients, and a personal history of cancer other than breast occurred in 20.74% of patients. The presence of PVs and VUS was evaluated, and 12.03% of patients were found to have a PV, with an average TC of 8.98%. The most common PVs were CHEK2, BRCA2, BRCA1, and BARD1. Out of those with PVs, 52% had non-BRCA1/2 PVs with an average TC of 5.47%. A total of 102 patients (10.58%) had a VUS, with an average TC of 8.29%. In further statistical analysis, TC were distributed significantly differently among the three groups, with differences observed between the BRCA group and negative group, as well as between BRCA and non-BRCA1/2 PVs group. A higher TC was also associated with BRCA1/BRCA2 variants compared to non-BRCA1/2 PVs. Conclusion: TC scores provide valuable information regarding the lifetime risk of an individual of developing breast cancer. However, the study found they were not associated with prediction of non-BRCA1/2 PVs. When choosing a genetic testing panel for breast cancer genes, TC is not as a reliable predictor on individual patient's family history, NCCN guidelines, or ASBrS guidelines. Our study supports the need to develop a genetic risk calculator that incorporates the predictive value for these non-BRCA1/2 PVs in otherwise low or average TC women.